: Selective serotonin (5-HT) reuptake inhibitors (SSRIs) such as fluoxetme (Prozac@) have revolutionized the treatment of many mood disorders. However, a major concern with SSRIs (and other antidepressants) is a 2-3 week delay in clinical improvement after the onset of treatment, which is associated with increased risk of suicides. The investigators studies demonstrate that SSRls reduce post-synaptic 5-HT1A receptor-mediated ACTH and oxytocin responses in a gradual manner, the timing of which is similar to the delayed therapeutic effects (7-14 days). These observations suggest that desensitization of hypothalamic post-synaptic 5-HTIA receptors may underlie some of the therapeutic effects of SSRIs. The investigators preliminary data suggest that this desensitization involves reductions in G2 proteins, which transduce 5-HT1A receptor signalling in the hypothalamus. The investigators hypothesis is that chronic exposure to SSRIs causes a sequence of adaptive changes in serotonergic neurotransmission, resulting in reduced 5-HT, receptor-G, protein signalling in the hypothalamus. The specific aims below will determine the role of serotonergic nerve terminals (aim 1), post-synaptic 5-HT1A (aim 2) and G, proteins (aim 3) in the sequence of adaptive changes induced by SSRIs. The appropriate molecular and biocheinical components of serotonergic signalling will be measured in each aim, including changes in hypothalamic levels of 5-HT, 5-HT1A receptor density, G2-protein levels and their degree of phosphorylation, and G2 mRNA. The function of hypothalamic 5-HT1A receptor systems will be determined from the neuroendocrine responses to specific 5-HT1A agonists. Aim 1 will determine the role of serotonergic nerve terminals in the hypothalamus in mediating fluoxetine-induced desensitization of post-synaptic hypothalamic 5-HT1A receptors. Aim 2 will determine the relative importance of somato-dendritic, compared with post-synaptic 5-HT1A receptors in fluoxetine-induced desensitization of hypothalamic post-synaptic 5-HTIA receptors. Aim 3 will determine: a) the role of hypothalamic G2 proteins in 5-HT1A receptor signalling (Aim 3a) and b) whether directly reducing the levels of G2 proteins in the hypothalamus, using antisense oligodeoxynucleotides, will shorten delay in fluoxetine-induced desensitization of hypothalamic 5-HTIA receptor function (Aim 3b). These studies will identify fundamental mechanisms responsible for SSRI-induced 5-HTIA receptor desensitization lay the foundation to discovering novel treatments of mood disorders with less delay in onset of therapeutic improvement.